The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Many cellular functions in both normal and transformed cells are linked to the maintenance of intracellular pH. Several investigators have recently shown that the proliferation activity of cancer cells can be modulated by agents that are capable of acidifying the cell cytosol (Cosentini et al. 2001, Wahl et al. 2002, Thangaraju et al. 1999). Analogously, intracellular acidification activates apoptosis or programmed cell death cascades (Gottlieb et al. 1996, Matsuyama et al. 2000). Acidification is postulated to affect key apoptotic enzymes such as acidic endonuclease causing DNA fragmentation and acidic sphingomyelinase producing ceramide (Gottlieb et al. 1996). Controlling of cell proliferation activity and apoptosis has consequently been identified as a promising approach for the pharmacological intervention in cancer (reviewed in Los et al. 2003). In the tumour bed, the cytosolic pH of the viable tumour cells is typically maintained close to neutral to facilitate proliferation, whereas the extracellular microenvironment is acidified by cellular metabolites (Yamagata & Tannock 1996).